Longitudinal studies in Parkinson's disease (PD), that document how changes in structure and function of the brain relate to changes in movement and cognition, represent a critical component to developing new therapies that will slow the rate of progression of PD. Unfortunately, longitudinal studies of brain structure and function in PD are very rare. In years 7-12 of this renewal R01, our laboratory is well-positioned to conduct a longitudinal study since we have already tested 40 patients with PD and 40 age and sex-matched control subjects at baseline. Our research team has used diffusion tensor imaging (DTI) to show that the structural integrity of the dorsal substantia nigra is reduced with age, and that the ventral substantia nigra is reduced in early stage, de novo PD. Further, our laboratory has used functional magnetic resonance imaging (fMRI) to show that the functional activity of all basal ganglia nuclei are reduced in PD during specific grip force switching tasks. We have shown that the functional activity of basal ganglia nuclei relates to specific motor signs in PD, such as bradykinesia and tremor. In this renewal, we will compare our baseline DTI and fMRI data in 40 de novo patients with PD and 40 control subjects longitudinally to a 4 year time point. In year 4, patients will be tested off and on antiparkinsonian medication. We test the hypothesis that alterations in the structural integrity of the substantia nigra and anterior thalamus are linked to disease progression changes in motor signs and cognitive signs. As a consequence, disease progression changes in motor signs and cognitive signs will be related to region-specific changes in functional activity of the basal ganglia, thalamus, motor cortex, and frontal cortex in PD. Aim 1a will use DTI to examine the structural integrity of the substantia nigra in relation to motor signs of PD. Aim 1B will use fMRI during a well-defined force switching task to examine the relation between functional activity of the basal ganglia, thalamus, and motor cortex to motor signs of PD. Aim 2a will use DTI to examine the structural integrity of the thalamus in relation to cognitive signs of PD. Aim 2b will use fMRI during a cognitive-motor task to examine the functional activity of the caudate and frontal cortex in relation to cognitive signs of PD. The proposed research is both significant and innovative because it will be the first comprehensive study to use structural and functional brain imaging at 3 Tesla to focus on how subcortical and cortical brain structures change in patients with PD after 4 years.